Hexose and pentose prodrugs of ethacrynic acid

ABSTRACT

A method of reducing intraocular eye pressure by topically applying to an affected eye a small but therapeutically effective intraocular eye pressure reducing amount of a compound which is a 2-deoxyglucose or hexose or pentose derivative of ethacrynic acid.

BACKGROUND OF THE INVENTION

Glaucoma, which some estimate affects 2 million adults over 40, is an impairment of vision caused by too much fluid pressure within the eye.

Surgical treatment for glaucoma is effective; however, it is expensive, and some surgeons will use surgery only as a last resort.

Glaucoma stems from an excess of fluid behind the cornea, the three-layered tissue that acts as a window to let light enter. Fluid-carrying nutrients, such as potassium and glucose, constantly wash the inside of the cornea to keep it healthy, much as tears wash the outside of the cornea.

In some middle-aged adults, fluids build up faster than can be absorbed back into the blood for one of two reasons: the ciliary body (a tiny tissue behind the iris) may excrete too much fluid, or the fluid may not drain off at the normal rate.

Either way, the excess fluid damages the optic nerve. At first a glaucoma victim usually experiences a subtle loss of peripheral vision--objects will seem to disappear from certain spots to the side. But glaucoma often leads to middle-age blindness.

Unfortunately, the two approaches to general drug usage in treating glaucoma--topical (dropped into the eye) and oral (through the mouth)--each have a peculiar set of side effects.

To make the long journey, oral drugs must be dosed in very high concentration. One class of drugs, called carbonic anhydrase inhibitors, slow the formation of fluid by inhibiting a chemical reaction at the ciliary body. Along with their well-tested effectiveness comes nausea, tingling in fingers and toes, and other side effects. Oral drugs generally do not, however, cause side effects in the eye, but the systemic delivery system is slow and causes other side effects.

From the above discussion, it can be seen that there is a continuing need for the development of new drugs that can be applied topically in order to avoid systemic effects, and which may at the same time still be highly effective. This, of course, necessitates that the compound be one which will, first of all, effectively evoke a response which will provide the correct intraocular pressure, and secondly, penetrate the cornea rapidly and distribute well to the active site, i.e. ciliary body of the eye or perhaps the trabecular meshwork. It goes without saying that compounds which are active as intraocular pressure inhibitors, but have limited penetrability across the cornea and to the site of activity are, as a practical matter, of limited value in developing truly effective topical glaucoma treatments, even though they may have some test activity in vitro, i.e. in a test tube. Put another way, if the compound does not have the correct distribution and penetration properties, its chances of being pharmacologically active, when topically applied to an affected eye in patients, are small at best. Thus, it is important if one is developing effective topical medicaments, that they be active in vitro, and that they be active when actually applied to an affected eye from the standpoint of penetrating the cornea and reaching the active site for effective treatment of glaucoma. There has been some work in the past with ethacrynic acid, but it has not proven effective in human models, even though it may have good pharmacological activity.

Accordingly, it is a primary object of the present invention to provide a new, highly effective topical treatment for glaucoma that has a surprisingly fast rate of absorption in comparison with ethacrynic acid, coupled with a demonstrated lack of toxicity risk and has demonstrated in vivo effectiveness.

It is another objective of the present invention to provide a new composition and new treatment using hexose and pentose prodrugs of ethacrynic acid for glaucoma that can be used topically to avoid many of the undesirable side effects of other currently available treatments.

It is another object of the present invention to provide new hexose and pentose derivatives of ethacrynic acid that are superior to ethacrynic acid as topical glaucoma treatments.

The method and manner of accomplishing each of the above objectives, as well as others, will become apparent from the detailed description of the invention which follows hereinafter.

SUMMARY OF THE INVENTION

Hexose derivatives of ethacrynic acid such as 6-ethacrynyl-2-deoxyglucose are used as effective topical glaucoma treatment agents. Pentose derivatives are used as well. They have a surprisingly high rate of absorption across the corneal tissue in comparison with ethacrynic acid.

DETAILED DESCRIPTION OF THE INVENTION

The hexose derivatives have the following formula: ##STR1## wherein R equals 2-deoxyglucose, a hexose or a pentose or positional isomers thereof. For 2-deoxyglucose, the positional isomers may be positioned at 1, 3, 4 and 6; for hexose the positional isomers may be at 1, 2, 3, 4 and 6; and for pentose the positional isomers may be at 1, 2, 3 and 5 positions. Typical examples of hexoses include glucose, arabinose and mannose. A typical example of a pentose includes ribose.

A preferred moiety for R is 2-deoxy glucose. These compounds, that is, the sugar esters of ethacrynic acid as reported here such as the hexoses and the pentoses are previously unreported in the literature and represent new compounds and new topical treatments for glaucoma. These compounds demonstrate unexpected topical effectiveness in comparison with ethacrynic acid. It is not known precisely why they are topically active for glaucoma treatment in comparison with ethacrynic acid. While applicant does not wish to be bound by any theory of operability, it is believed that they have the proper combination of absorption rate of the prodrug and cleavage to the active species, ethacrynic acid, which exerts the potent therapeutic effect. In any event, they are unexpectedly superior in topical application and therefore effectiveness in comparison with ethacrynic acid.

In conjunction with the evaluation of the present invention and its unexpected results, it is important to distinguish between topical application for treating glaucoma and oral dosing for treating glaucoma. This has been mentioned previously, but it is emphasized here again that topical application (dropped into the eye) has the significant advantage of avoiding most of the systemic side effects, but for effectiveness it is essential that the compound or compounds be transported into the eye at sufficient levels to reach the proper receptor site. Thus, topically active compounds must have the correct distribution and penetration properties. Ethacrynic acid, and most of its ester analogues, while perhaps having some activity in oral administration, do not exhibit such activity topically. In this respect, the hexose and pentose and deoxyglucose derivatives appear to be peculiarly unique in that they have highly effective pharmacological properties, and at the same time are topically active.

Typically, the method of administration is simply preparing an ointment (such as petrolatum) or gel with a conventional pharmaceutical carrier (such as carbopol) and topically administering the gel composition. The amount of active use in the composition should be from about 0.25% by weight to about 5% by weight for an eye drop composition, preferably from about 0.5% by weight to about 2.0% by weight. The important point is not the dose amount, but simply that it be an amount that is effective in treating glaucoma and yet not be so strong as to provide eye irritation or side effects. Generally, amounts within the ranges herein specified are satisfactory.

Assuming a stable ester analogue, the carrier for the eye drop composition may be an isotonic eye treatment carrier buffered to a pH of from about 4 to about 8, and typically it will contain small amounts of conventional wetting agents and anti-bacterial agents. The preferred pH is within the range of from about 6.8 to about 7.8 and contains sufficient sodium chloride or equivalent to be isotonic. Anti-bacterial agents where they are included may be within the range of from about 0.004% (W/V) to about 0.02% (W/V) of the composition.

The ophthalmically active compounds may be incorporated into various ophthalmic gel formulations for delivery to the eye. In order to form sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active nonsteroidal drugs of this invention in a hydrophilic base prepared from a combination of carbopol -940 (a carboxy vinyl polymer available from the B. F. Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can also be incorporated.

EXAMPLES

The following examples are offered to illustrate the preparation of 6-ethacrynyl-2-deoxy-α-D-arabinohexopyranoside, sometimes referred to as 6-ethacrynyl-2-deoxyglucose and its effective use topically.

1-Benzyl-2-deoxy-α-D-arabinohexopyranoside

One equivalent of 2-deoxyglucose was suspended in 165 ml. of benzyl alcohol and cooled in an icebath. Anhydrous hydrogen chloride was bubbled through the stirred mixture for five minutes, the icebath removed, and the mixture stirred overnight. Dichloromethane (200 ml) was added to the clear solution and sodium bicarbonate neutralized the excess acid. After two hours of stirring, the salts were removed by paper filtration. The dichloromethane and the excess benzyl alcohol were by vacuum distillation. The solid residue was recrystallized from acetone-ethanol (1:1) to yield a white solid.

1-Benzyl-6-ethacrynyl-2-deoxy-α-D-arabinohexopyranoside

Ethacrynic acid (5.5 μmol.), thionyl chloride (11 μmol.), and 15 ml. of chloroform were refluxed overnight and the excess thionyl chloride and chloroform removed in vacuo. The ethacrynyl chloride was dissolved in 5 ml. of anhydrous tetrahydrofuran (THF) and added dropwise to a stirring solution of 1-benzyl-2-deoxy-α-D-arabinohexopyranoside (5 μmol.) and 4-dimethylaminopyridine (5.5 μmol.) in 10 ml THF. The reaction mixture was stirred for four hours and the solids removed by paper filtration. The filtrate was evaporated in vacuo and purified by silica gel chromatography, eluting with hexane/ethyl acetate (1:1).

6-Ethacrynyl-2-deoxy-α-D-arabinohexopyranoside

1-Benzyl-6-ethacrynyl-2-deoxy-α-D-arabinohexopyranoside (0.5 g.) was dissolved in 30 ml. of dry methylene chloride and cooled in a dry ice/acetone bath. To the cold, stirred solution was added 10 ml. of 1.0M boron trichloride in methylene chloride. After stirring for 0.5 hr. after the dropwise addition, the reaction was quenched by the addition of 10 ml. of diethyl ether, warmed to room temperature, and stirred an additional 1.0 hr. After water was added to quench the mixture, it was extracted with three 40 ml. portions of ethyl acetate. The combined ethyl acetate extracts were washed twice with 20 ml. portions of saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was dried over sodium sulfate, evaporated in vacuo, and purified by chromatography (silica gel/chloroform-methanol, 9:1). The product, m.p. 140°-2° C., possessed proton nuclear magnetic resonance spectra, electron impact mass spectra, and combustion analysis of carbon, hydrogen, and nitrogen consistent with assigned structure.

The recovered 6-ethacrynyl-2-deoxy glucose was used topically as described below in the "IOP recovery rate assay" analysis.

The "IOP recovery rate assay", as reported by Vareilles and Lotti (Ophthal. Res., 13, 72-79, 1981), was used. In this assay 20% sodium chloride solution was infused into the marginal ear vein of New Zealand White rabbits for 10 minutes at a rate of 1 mL/min (N=12). IOP was measured at 15, 25, 35, 45, 60, 75, 90 and 120 minutes with an applanation pneumatonometer (Alcon Digilab Model D). Fifty μL of a 2% solution or suspension of new drug agents containing a pH 7.4 phosphate buffer was administered topically to the right eye 60 minutes before the start of the sodium chloride infusion. Control animals were given vehicle without drug.

The average (±standard deviation) slope values for 10-12 rabbit eyes were as shown in Table I.

                  TABLE I                                                          ______________________________________                                                   Avg. Drug   Ave. Blank                                               TEST      Treated     Treated Rabbits                                                                            % Decrease                                   COMPOUND  Rabbits (slope)                                                                            (slope)     in Slope                                     ______________________________________                                         Ethacry-  0.0673 ± 0.0179                                                                         0.0752 ± 0.0176                                                                         10.5                                         nic acid                                                                       6-Ethacry-                                                                               0.0599 ± 0.0183                                                                         0.0910 ± 0.0340                                                                         34.2                                         nyl-2-de-                                                                      oxy glucose                                                                    ______________________________________                                    

The hypertonic sodium chloride solution causes a temporary decline in IOP which returns to normal IOP in about 90 minutes if no drug is administered. IOP gradually returns to normal at a constant rate, but more slowly if the in vivo secretion rate of aqueous humor is reduced due to the presence of drug. The return to normal IOP is measured from the positive linear slope, which is a measure of the constant rate of return to normal IOP, and begins at about 30-45 minutes after starting the NaCl infusion. A comparison of the slope with and without the addition of test agent to the rabbit eye is expressed as "% decrease in slope".

From the above tests, it can be seen that the 6-ethacrynyl-2-deoxyglucose was effective in comparison with ethacrynic acid compound which had previously been reported as active in an animal model, but recently failed in human trials. Much greater penetration ability of 6-ethacrynyl-2-deoxyglucose indicates that in spite of recent failed tests in human models for ethacrynic acid itself, 6-ethacrynyl-2-deoxyglucose would be effective.

In the above example, when other hexose and pentose derivatives are substituted for the 6-ethacrynyl-2-deoxyglucose, substantially similar results are achieved in that they are demonstratively superior to ethacrynic acid for topical use in glaucoma treatment.

It therefore can be seen that the invention accomplishes at least all of its stated objectives. 

What is claimed is:
 1. A method of reducing intraocular eye pressure, said method comprising:topically applying to an affected eye a small but therapeutically effective intraocular eye pressure reducing amount of a compound selected from the group consisting of 2-deoxyglucose ester derivatives, hexose ester derivatives and pentose ester derivatives of ethacrynic acid.
 2. The method of claim 1 wherein the active compound selected from the group consisting of 2-deoxyglucose derivatives, hexose derivatives and pentose derivatives of ethacrynic acid is dosed from an eye drop composition containing from about 0.25% by weight to about 5% by weight of the active in the eye drop composition.
 3. The method of claim 1 wherein the eye delivery composition is an ointment composition, either aqueous or oleaginous.
 4. The method of claim 2 wherein the dose amount is from about 0.5% by weight to about 2% by weight of said composition.
 5. An eye ointment treatment which comprises:an ointment suspension of a small but therapeutically effective intraocular eye pressure reducing amount of the compound selected from the group consisting of 2-deoxyglucose ester derivatives, hexose ester derivatives and pentose ester derivatives of ethacrynic acid in a pharmaceutically acceptable ointment carrier.
 6. The composition of claim 5 wherein the amount of 2-deoxyglucose ester derivatives, hexose ester derivatives and pentose ester derivatives of ethacrynic acid in the ointment composition is from about 0.25% by weight to about 5% by weight of the eye ointment composition.
 7. The composition of claim 6 wherein the dose amount is from about 0.5% by weight to about 2% by weight of said ointment composition.
 8. The method of claim 1 wherein the active compound is 6-Ethacrynyl-2-deoxyglucose.
 9. The method of claim 2 wherein the compound is 6-Ethacrynyl-2-deoxyglucose.
 10. The composition of claim 5 wherein the compound is 6-Ethacrynyl-2-deoxyglucose. 